GB1592201A - Heteroaromatic polymer ultrafiltration membranes - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 592 201

-.I ( 21) Application No 39135/77 ( 22) Filed 20 Sept 1977 ( 31) Convention Application No 728453 ( ( 32) Filed 29 Sept 1976 in ( 33) United States of America (US) ( 44) Complete Specification published I July 1981 ( 51) INT CL 3 BOID 13/04 C 08 J 5/18 ( 52) Index at acceptance B 5 B 361 369 902 FB ( 54) HETEROAROMATIC POLYMER ULTRAFILTRATION MEMB RANES ( 71) We, PHARMACO INC, a Corporation organized and existing under the Laws of the State of Illinois, United States of America of 1616 Interstate Drive, Champaign, Illinois, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to

be performed, to be particularly described in and by the following statement: 5

Ultrafiltration of solutions through microporous membrane filters is an old and well established method Numerous types of materials ranging from animal membranes to synthetic organic polymers and many different processes of forming these microporous membranes have been described in the literature Several reviews on ultrafiltration have been published (J D Ferry, Chemical Reviews, Vol 10 18, ( 3), pp 373-455 ( 1936); A S Michaels, Progress in Separation and Purification, Vol 1, 297 ( 1968); C J Van Oss, Purification and Separation, Vol 3, 97 ( 1972)).

Various types of ultrafilters are being used in commercial processes for performing separations and concentrations of various solutes from their respective 15 solutions Loeb type membranes made of cellulose diacetate are described in United States Patents Nos 3,133,132 and 3,133,137 Microporous membranes based on other types of polymeric materials including the utilization of polysulfone, cellulose butyrate, cellulose nitrate, polystyrene and other polymers are disclosed in United States Patent No 3,676,203 Other related patents cited for reference are 20 United States Patents Nos 3,556,992, 3,579,412, 3,228,876, 3,364,288, and 3,173,836, Dutch Patent No 74,531 and French Patent Nos 555,471 and 1,075,417 Various ultrafiltration membranes used in commercial processes are marketed under the trade names of "Millipore" by Millipore Corporation, "Unipore" by Bio Rad Laboratories, "Diaflo" by Amicon Company and "Nucleopore" by Nucleopore 25 Corporation.

When utilizing ultrafiltration membranes in such applications as the treatment of waste effluents, the separation and purification of biological fluids, the clarification of colloidal solutions and the sizing of molecules, it is desirable that the ultrafilter be resistant to compaction under pressure, insensitive to p H of the 30 feed solution, unaffected by the solvent used and be stable at elevated temperatures It is also advantageous that the membrane filter not be affected by repeated drying and rewetting (i e stable to wet-dry cycling) with the feed solution.

In the quantitative separation and sizing of solute molecules of widely different molecular weights it is of utmost importance that the surface pores are of nearly the 35 same size (i e, isoporous) and that the size of surface pores can be varied over a wide range from a few angstroms to several thousands of angstroms None of the membranes cited in the previous art fulfill all these requirements.

According to the present invention there is provided a membrane consisting of a microporous structure having semipermeable properties, said membrane having 40 been formed by contacting a film made from a solution containing a heteroaromatic polymer with a nonsolvent or mixture of nonsolvents in which said polymer is essentially insoluble, said polymer having the recurring structure of one of the following formulae or its substituent position isomers or heretoatom ring position isomers: 45 1,592,201 R -n X N fit Re N R -n (A) (B) (C) (D) y (E) (F) wherein R is phenylene, diphenylene, diphenyl ether, diphenylsulfide, diphenyl sulfone, diphenylmethane, naphthylene, pyridylidene or alkylene of I to 6 carbon atoms, R' is hydrogen, an aromatic radical or an aliphatic radical, X is a carbon-tocarbon bond, oxygen, sulfur, sulfone, methylene, isopropylidene, carbonyl, a pyridylidane group or a diphenyl ether residue and N is 10 to 10,000.

3 12 The heteroaromatic polymers to be used in accordance with this invention to form microporous membranes include poly as triazines which are characterized by the recurring structural formula:

N N N N and/or isomers as defined above Example in N N N N (Structure I) wherein X is a carbon-to-carbon bond, oxygen, sulfur, sulfone, methylene, isopropylidene, carbonyl, a pyridylidene group or a diphenyl ether residue, R' is a hydrogen atom, an aliphatic group such as an alkyl radical having 1 to 12 carbon atoms or an aromatic group such as a phenyl or toluyl radical, R is a divalent radical consisting of groups such as phenylene, diphenylene, diphenyl ether, diphenylsulfide, diphenyl sulfone, diphenylmethane, naphthylene, pyridylidene or alkylene having 1 to 6 carbon atoms, and N is 10 to 10,000 Preferably, the poly as triazines as well as the other heteroaromatic polymers used in accordance with this invention have a molecular weight greater than 20,000.

Other heteroaromatic polymers useful in forming microporous membranes in accordance with this invention are polyquinoxalines having the following repeating units:

and/or isomers as defined above.

Example

R'=Hydrogen Structure II R'=C 6 Hs Structure III and poly (pyrazinoquinoxalines) having the recurring structural formula:

1,592201 A 4 1,9 X O LI wherein X, R, R' and N are the same as defined with respect to the poly as triazines.

Yet other heteroaromatic polymers useful in forming microporous membranes in accordance with this invention are polyquinolines having the following repeating units:

and/or isomers as defined above.

Example (Structure IV) and poly (anthrazolines) having the recurring structural formulas:

n R An wherein X, R, R' and N are the same as defined with respect to the poly as triazines.

The invention also contemplates incorporating covalently bonded groups into the heteroaromatic polymers discussed above by treating the polymers either before or after quenching with appropriate reactants The covalently bonded groups include sulfonic acids such as derived from chlorosulfonic acids, hydroxy groups, carboxylic acids, mercaptans and amines Preferably, the heteroaromatic 1,592,201 A 1,592,201 5 polymers have at least one of the covalently bonded groups for every chain length interval of six heteroatomatic radicals Additionally, the invention contemplates employing heteroaromatic copolymers formed by copolymerizing the heteroaromatic polymers discussed above or their monomers.

This invention also comprises a method of preparing an ultrafiltration 5 membrane by dissolving a hetero aromatic polymer as defined above fordning a polymer solution of the above heteroaromatic polymers in which the concentration of polymer is preferably at least 2 weight percent and not in excess of weight percent The polymer solution is then cast to a finite thickness and the wet film is caused to gel by quenching into an appropriate nonsolvent in which the 10 polymer shows a tendency to swell, coagulate or precipitate The solution casting operation may be carried out on either nonporous substrates such as glass plates or stainless steel belts or on porous substrates such as paper, fabric, etc In the case of nonporous substrates the membrane separates from the film supporting substrate, while in the case of porous substrates the substrate becomes an integral part of the 15 ultrafilter.

The solvents which may be used to form the polymer solutions of the heteroaromatic polymers include aromatic solvents such as cresols, preferably metacresol, aliphatic hydrocarbons and particularly halogenated aliphatic hydrocarbons such as chloroform, methyl chloroform, tetrachloroethane and 20 methylene chloride, aliphatic amides such as dimethylacetamide and inorganic acidic solvents such as sulfuric acid and methane-sulfonic acid The nonsolvents which may be used in the quenching bath include aliphatic alcohols and particularly lower alkanols such as methanol, ethyl alcohol, isopropyl alcohol and amyl alcohol, aliphatic hydrocarbons, aromatic hydrocarbons such as toluene, 25 aliphatic ketones, aliphatic aldehydes, aliphatic nitriles, and aqueous baths including aqueous solutions of organic bases and acids.

A particular feature of the invention and one that emphasizes its simplicity is that the gelation process requires no particular control of the environment in which the membrane is formed Generally, ambient conditions without any particular 30 atmosphere control suffice to make membranes of uniform porosity and pore size.

Another simplifying feature of the membrane formation process described in this invention is that reproducible and uniform membranes are obtained without any particular control of process variables such as casting speed, quench angle and j 5 quench bath temperature It is believed that the insensitivity of membrane 35 formation towards environmental and process conditions lies in 1) the thixotropiclike nature of the polymer solutions wherein the heteroaromatic polymers act as weak bases to the acidic solvents employed such as meta-cresol, and wherein the viscosity of these strongly interacting solute-solvent systems does not significantly 40 change within the ordinarily encountered temperature fluctuations of a room; 2) the low affinity of these heteroaromatic polymers and solvents such as cresols and chlorinated hydrocarbons toward moisture in the air; and 3) the extreme rapidity with which the heteroaromatic polymers precipitate when solutions of these polymers come in contact with the proper nonsolvents in the quench bath.

These fast gelation rates are believed to be due to the extreme insolubility of the heteroaromatic polymers used in this invention towards the liquids or vapors of these liquids used for quenching such as alcohols, hydrocarbons, ketones and also due to the relatively low interfacial tension between the solvents and nonsolvents used in this invention In this respect it is the extreme insolubility of these polymers towards liquids such as alcohols, ketones, hydrocarbons, aldehydes, nitriles and 50 aqueous solutions of organic bases and acids that renders membranes made from these polymers insensitive towards these liquids and makes it possible to utilize such solvents for ultrafiltration.

Other remarkable features of the heteroaromatic polymers used in this invention are their exceptional thermal and mechanical stabilities For example, the polymers used in this invention all exhibit heat distortion temperatures above 2500 C and some polymers such as the polyphenylquinoxalines show heat distortion temperatures in excess of 350 C These temperatures lie 100-200 C above those of polymers used for the formation of ultrafiltration membranes in accordance with 60 the prior art Therefore membranes made from these heteroaromatic polymers are capable of operation at elevated temperatures where previous membranes are subject to thermal distortion and collapse of pores.

Yet another important feature of the present invention is the case with which the pore size of the membrane can be varied over a wide range from a few angstroms to hundreds of angstroms by varying simple casting parameters such as 65 the nature of the solvent, the type of nonsolvent or the concentration of the polymer in the casting solution Also, membrane properties can be readily controlled by the addition of salts such as alkali metal salts, for example, lithium chloride and sodium chloride and Group IIB metal salts, for example, zinc chloride and by the addition of surfactants Typical surfactants are sodium dodecyl sulfate 5 and alkylaryl polyether alcohols such as sold under the trademarks "NP-40 W (Shell Chemical Co) and "Triton X-100 " (Rohm & Haas Co) "NP-40 " is an octaphenyl ethoxylate containing approximately 9 moles of ethylene oxide in the polymer chain and "Triton X- 100 " is similarly a condensation product of octaphenyl and ethylene oxide 10 This invention also comprises generating a highly asymmetric structure which consists of an ultrathin barrier film of the desired pore size which is supported by a highly porous substructure This membrane structure provides for maximum flow of solvent with a minimum amount of plugging by the material being filtered This is due to the absence of long and/or tortuous channels found in all other 15 ultrafiltration membranes This microporous structure is formed by employing a combination of solvents such as chloroform and meta-cresol, tetrachloroethane and meta-cresol, methyl chloroform and meta-cresol, methylene chloride and meta-cresol, tetrachloroethane and phenol, methyl chloroform and phenol and methylene chloride and phenol which, due to the evaporation of the low boiling 20 component, causes a rapid interfacial skin formation The polymer is then quenched into nonsolvents wherein the bulk of the membrane is allowed to gel For example, by using this technique asymmetry factors are easily obtained in which the ratio of bulk pore size to surface pore sizes is 6000:1.

The ultrafiltration membranes of this invention may be used for in-line 25 filtration of intravenous infusions without requiring pressure devices More particularly, the ultrafilters of this invention have such extremely small surface pore size and still have such acceptable solution flow rates that the filters not only remove inanimate particulate contaminants but also bacteria and viruses Other examples of uses are: 1) concentration of filtration of dilute protein solutions by 30 using simple hand operated syringes; 2) concentration or filtration of industrial protein preparations; 3) filtration of bulk fluids for intravenous solutions (large volume parenterals) on the industrial scale; 4) filtration and/or clarification of beverages (wine, beer, etc), syrups, etc; 5) filtration of drug solutions prior to packaging; and 6) preparation of sterile, particle free water and aqueous chemical 35 solutions.

The following examples are given to illustrate the various types of ultrafiltration membranes and the process of the present invention, but, however, are not intended to limit the scope of the invention as defined in the appended claims 40 Example 1

A solution containing 8 5 weight percent of polyphenyl as triazine (Structure I) in meta-cresol is spread onto a glass plate by means of a solution casting knife of 0 02 inch knife gap The wet film is allowed to remain on the glass plate for a period of 10 minutes Then the glass plate is immersed into a quenching 45 bath containing a mixture of 50 volume percent ethyl alcohol and 50 volume percent of toluene After a period of 20 seconds the film becomes opaque and is allowed to remain in the bath for an additional period of 30 minutes The resulting ultrafiltration membrane is then stored in a mixture of 20 vol percent ethyl alcohol and 80 vol percent distilled water This membrane has a water flux of 1 896 x 10-8 50 cc/dyne-sec, a specific water content of 0 578 g/cm 3, an average pore size of 20 to A and a membrane thickness of 005 cm.

When used as an ultrafilter, the membrane described above passes salts such as sodium chloride, sodium phosphate, calcium sulfate, and low molecular weight compounds such as phenol red, fluorescein, p-aminobenzoic acid hydrochloride, 55 acriflavin hydrochloride, and ribonuclease without loss or change in concentration.

However, higher molecular weight compounds such as double stranded DNA with molecular weights of about 10,000 and higher, Dextran 200 and Dextran 2000 (blue), and proteins such as bovine serum albumin and hemoglobin are retained by the filter 60 A summary of ultrafiltration data obtained for this membrane is shown in the

Table.

I 1,592,201 7 1,592,201 7 TABLE

Ultrafiltration of various solutions through polyphenyl as triazine membranes with a pore size of about 30 A Feed Additive % Solute Molecular Concentration To In UltraSolute Weight (?/) Solvent Solvent filtrate Phenol Red 001 water none 100 Fluorescein 10-4 water none 100 Fluorescein 10-8 water none 0 Fluorescein 10- water SDS 100 Fluorescein 10-8 water TCA 100 Dextran 10,000 1 water none 88 Ribonuclease 13,000 10-4 1 M phosphate none 99 buffer Dextran 20,000 1 water none 55 Dextran 40,000 1 water none 50 Dextran 200,000 1 water none 0 H 3-TTP 10-8 1 M Phosphate none 98 Hemoglobin 68,000 2 Phosphate none 0 Bovine serum albumen 69,000 2,, none 0 ss-DNA 10,000,,,, none 5 ss-DNA 10,000,,,, SDS 100 ss-DNA 10,000,,,, TCA 96 ss-DNA 1,300,000,,,, none 5 ds-DNA 1,300,000,,,, none 86 ss-DNA 500,000,,,, none 3 ds-DNA 500,000,,,, none 94 RNA 20,000,,,, none 95 RNA 300,000,,,, none 0 RNA 300,000,,,, SDS 79 RNA 1,300,000,,,, SDS 18 DNA=Deoxyribonucleic acid, TTP=Thiamine Triphosphate, TCA=Trichloroacetic Acid.

RNA=Ribonucleic acid, SDS=Sodium Dodecyl Sulfate, Example 2

The above formulation may be modified by adding nonsolvents to the polymer casting solution, resulting in membranes of increased porosity and pore size.

A solution of 8 5 weight percent of poly -, phenyl as trazine (Structure I) in 50/50 vol percent of meta-cresol and toluene was cast into an ultrafiltration membrane as described in Example 1, except that the quench bath contained a mixture of 95 vol percent ethyl alcohol and 5 vol percent water.

The membrane thus obtained had a thickness of 0 03 cm, a specific water content of 0 662 g/cm 3, a water flux of 1 68 x 10-7 cc/dyne-sec, and an average pore size of 40 A In contrast to the membrane described in Example 1, the membrane of Example 2 allows the passage of the protein bovine serum albumin (M W 69, 000) without loss or change in concentration.

Example 3

The membrane as described in Example 1 may further be modified by the addition of surfactants to the polymer casting solution.

Sodium dodecyl sulfate, 0 2 weight percent, is added to a solution of 8 5 weight percent of poly phenyl as triazine (Structure I) in meta-cresol as solvent, by slowly adding the surfactant at 45 C with moderate stirring This polymer solution is cast into an ultrafiltration membrane as described in Example 1 The ultrafiltration properties of this membrane are similar to the one described in Example 1, except that the membrane of Example 3 is completely stable with respect to water flux after repeated drying for several days followed by rewetting with water.

1,592,201 Example 4

The membrane of Example I may further be modified by the addition of salts.

Poly phenyl as triazine (Structure I), 11 3 g, is dissolved in a mixture of 45 g of meta-cresol and 60 g of dimethylacetamide to which 4 5 g of lithium chloride has been added This solution is cast onto a glass plate by means of a casting knife 5 with a knife gap of 0 02 inch The wet film is immediately placed into a bath containing a mixture of 60/40 vol percent of methanol and water After a period of seconds the film becomes opaque and the remaining solvents and salt is leached out of the film by repeated washing with methyl alcohol followed by rinsing with distilled water The ultrafiltration membrane thus obtained has a water content of 10 0.598 g/cm 3 and a membrane thickness of 0 061 cm When used as an ultrafilter this membrane exhibits strong anisotropic flow behavior toward serum albumin and dyes For example, the shiny skinned surface does not absorb phenol red, while the dull surface absorbs the dye very strongly Ultrafiltration of serum albumin with the skinned surface towards the protein solution results in complete rejection of the 15 solute On the other hand filtration with the dull surface towards the protein solution results in partial passage of the protein molecules.

Example 5

Poly-quinoxaline (Structure II) is dissolved in meta-cresol to obtain an 8 weight percent solution A small amount of undissolved polymer is removed by 20 filtering the solution through a 10 micron polypropylene filter The clear filtrate is cast onto a glass plate by means of a casting knife with a knife gap of 0 02 inch The glass plate is immediately immersed into a bath containing methyl alcohol, forming the opaque ultrafilter The membrane is stored in a sterile solution containing 0 5 percent formaldehyde in distilled water The ultrafilter obtained in this way had a 25 thickness of 0 038 and a water flux of 6 51 x 10-8 cc/dyne-sec Ultrafiltration of ribonucleic acid solutions containing low and high molecular weight fractions through this membrane resulted in a near quantitative separation of the low from the higher molecular weight material.

Example 6 30

Polyphenylquinoxaline (Structure III), 14 6 g, was dissolved in 200 cc of chloroform The resulting solution was cast onto a glass plate by means of a casting knife ( 0 02 inch knife gap) and the surface of the wet film was exposed to the vapors of methyl alcohol causing slow gelation of the polymer film The gelled film was then dipped into a solution of 50 vol percent hexane and 50 vol percent toluene to 35 remove any residual chloroform and methanol from the interior of the membrane.

This procedure was followed by several washes with methyl alcohol to remove the hexane and toluene Finally, the membrane was stored in a mixture of 10 vol.

percent methanol and 90 vol percent water The membrane obtained had a thickness of 0 45 cm, a water flux of 0 36 x 10-8 cc/dyne-sec, and an average pore 40 diameter of 19 A.

Example 7

Polyquinoline (Structure IV) was dissolved in chloroform to obtain a 10 weight percent solution A film of this material was prepared as described in Example I and quenched into a bath containing methyl alcohol After a period of 2 hours the 45 opaque film membrane was removed from the quench bath and stored in a solution of 20 vol percent methyl alcohol and 80 vol percent water The membrane thus obtained had a thickness of 0 065 cm and a low pressure membrane constant of 2.7 x 10-8 cc/dyne-sec.

A portion of this membrane was modified by treating it with a 0 11 %, solution of 50 methanesulfonyl chloride in hexane for a period of 2 minutes, followed by exposure to water for a period of 20 minutes This modification resulted in a membrane with a water flux of 5 83 x I 08 cc/dyne-sec.

Example 8

A solution containing 10 0 g of polyphenyl as triazine (Structure I) and 10 0 g 55 of polyphenylquinoxaline (Structure III) was dissolved in a mixture of 50 vol.

percent sulfuric acid and 50 vol percent methanesulfonic acid to obtain a 10 weight percent solution The solution was then spread onto a glass plate by means of a casting knife with a 0 02 inch gap The glass plate was then immersed into a water bath which solidified the wet film instantly The ultra-filtration membrane thus 60 obtained exhibited a water flux of 1 90 cc/dyne-sec.

I 1,592,201 F 9 1,592,201 9 Example 9

A copolymer of polyquinoxaline (Structure II) and polyphenylquinoxaline (Structure III) ( 30-70 random copolymer) was dissolved in meta-cresol to form a 6 weight percent solution An ultrafiltration membrane was then made from this solution as described in Example 1 The membrane exhibited a water flux of 5 3.2 x 10-8 cc/dyne-sec and had a pore size of 30 A.

Example 10

A 15 % solution of polyphenylquinoxaline (Structure III) in a 50/50 volume ratio of m-cresol and chloroform was cast onto a Dacron cloth using a 15 mil knife gap between the cloth and the knife Then the wet impregnated fabric was 10 quenched into isopropyl alcohol and the solvent allowed to leach out, leaving a reinforced ultrafilter which gave a water flux of 4 cc/min/cm 2 of filter area at an applied pressure of 2 psig.

Claims (1)

1. WHAT WE CLAIM IS:-

   1 A membrane consisting of a microporous structure havaing semipermeable 15 properties, said membrane having been formed by contacting a film made from a solution containing a heteroaromatic polymer with a nonsolvent or mixture of nonsolvents in which said polymer is essentially insoluble, said polymer having the recurring structure of one of the following formulae or its substituent position isomers or heteroatom ring position isomers: 20 / XA N N n (A) X N''R ' N J R A /" N N I J (D) n 1,592,201 to RI RI (E) N /v\ N t R n N R 4 I < O (F) N "R wherein R is phenylene, diphenylene, diphenyl ether, diphenylsulfide, diphenyl sulfone, diphenylmethane, naphthylene, pyridylene or alkylene of I to 6 carbon atoms, R' is hydrogen, an aromatic radical or an aliphatic radical, X is a carbon-to 5 carbon bond, oxygen, sulfur, sulfone, methylene, isopropylidene, carbonyl, a pyridylidene group or a diphenyl ether residue and N is 10 to 10,000.

   2 A membrane as claimed in claim 1, in which R' is hydrogen, phenyl, toluyl or alkyl of from I to 12 carbon atoms.

   3 A membrane as claimed in claim 1, in which said polymer comprises a 10 poly as triazine having the recurring structure of formula (A) in claim 1.

   4 A membrane as claimed in claim 1, in which said polymer comprises a polyquinoxaline having the recurring structure of formula (B) in claim 1.

   A membrane as claimed in claim 1, in which said polymer comprises a poly (pyrazinoquinoxaline) having the recurring structure of formula (C) in claim 1 15 6 A membrane as claimed in claim 1, in which said polymer comprises a polyquinoline having the recurring structure of formula (D) in claim 1.

   7 A membrane as claimed in claim 1, in which said polymer comprises a poly (anthrazoline) having the recurring structure of formula (E) or (F) in claim 1.

   8 A membrane as claimed in any preceding claim, in which said polymer has a 20 molecular weight greater than 20,000.

   9 A membrane as claimed in claim 1, in which said polymer consists of a chain having two or more different recurring structures.

   A membrane as claimed in claim I in which said polymer solution comprises a mixture of two or more of said heteroaromatic polymers 25 11 A membrane as claimed in any preceding claim, in which said polymer includes covalently bonded groups incorporated therein, said groups being sulfonic acids, hydroxyl groups, carboxylic acids, mercaptans or amines, said polymer having at least one of said covalently bonded groups for every chain length interval of six heteroaromatic radicals 30 12 An intravenous fluid filtration or concentration apparatus for filtering or concentrating intravenous fluid comprising a filter for removing inanimate particulate contamination and for concentrating said fluid, said filter comprising a membrane as claimed in any preceding claim.

   13 Apparatus as claimed in claim 12, in which said membrane has a pore size 35 which will remove bacteria and viruses.

   14 Apparatus as claimed in claim 12 or claim 13, in which said apparatus is an intravenous set for supplying intravenous fluid to a patient.

   An apparatus for concentrating and filtering protein solutions, comprising an in-line filter for filtering out undesirable impurities and for concentrating said 40 solutions, said filter comprising a membrane as claimed in any of claims I to 11.

   16 Apparatus as claimed in claim 14, in which said apparatus comprises a syringe having said membrane associated therewith.

   17 An apparatus for filtering and clarifying beverages and the like comprising an in-line filter for filtering out undesirable impurities and for clarifying said 45 beverages, said filter comprising a membrane as claimed in any of claims 1 to 11.

   18 Apparatus as claimed in claim 17, in which said beverages are wine, beer or syrups.

   19 An apparatus for filtering drug solutions prior to packaging comprising an in-line filter comprising a membrane as claimed in any of claims I to 11 50 An apparatus for preparing sterile, particle free water and aqueous chemical solutions, the improvement comprising an in-line filter comprising the membrane of claim 1.

   21 A method of making an ultrafiltration membrane comprising dissolving a heteroaromatic polymer as defined in claim 1 or claim 11 in a solvent, casting a 5 liquid film of said dissolved polymer and contacting said film with a nonsolvent to cause said film to solidify.

   22 A method as claimed in claim 21, in which the concentration of polymer in said solvent is at least 2 weight percent and not in excess of 30 weight percent.

   23 A method as claimed in claim 21, in which said solvent is sulfuric acid or 10 methanesulfonic acid and said nonsolvent is water.

   24 A method as claimed in claim 21, in which said solvent is a cresol and said nonsolvent is an aliphatic or aromatic hydrocarbon.

   A method as claimed in claim 21, in which said solvent is a chlorinated hydrocarbon selected from chloroform and tetrachloroethane and said nonsolvent 15 is an aliphatic alcohol, ketone or aldehyde.

   26 A method as claimed in any of claims 21 to 25, in which said liquid film is allowed to develop a skinned surface by partially evaporating said solvent, saidskinned film being subsequently contacted with said nonsolvent.

   27 A method as claimed in any of claims 21 to 26, in which said liquid film is 20 exposed to the vapors of said nonsolvent, thereby causing said liquid film to solidify.

   28 A method as claimed in any of claims 21 to 27, in which said nonsolvent is added to said polymer solution prior to membrane formation in such a quantity as to prevent said polymer from precipitating from said solution and in an amount not 25 exceeding 70 volume percent of said solvent 29 A method as claimed in any of claims 21 to 28, in which a surfactant is added to said polymer solution.

   A method as claimed in claim 29, in which said surfactant is sodium dodecyl sulfate 30 31 A method as claimed in any of claims 21 to 30, in which a salt selected from the group consisting of mono-, di-, and trivalent cations is added to said polymer solution prior to contacting said solution with said nonsolvent.

   32 A reinforced ultrafilter comprising a membrane as defined in claim I formed on the surface of a reinforcement, said reinforcement being a woven or 35 non-woven fabric or paper.

   33 A membrane substantially as described herein with reference to any one of the Examples.

   34 A method of marking a membrane substantially as described herein with reference to any one of the Examples 40 Agent for the Applicants:

   WILSON, GUNN & ELLIS, Chartered Patent Agents, 41-51 Royal Exchange, Manchester, M 2 7 DB.

   Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A IAY, from which copies may be obtained.

   lo 1 1,592,201